In order to account for the remarkable catalytic power of enzymes, it is generally considered that the activation free energy is contributed both by binding of the substrate to the enzyme (step 1) and by chemical manipulation of the bound substrate (bond-making and breaking, step 2). Popular opinion holds that most of the activation energy is supplied in step 2: We have proposed, however, that the over all catalytic process can be explained more reasonable if it is assumed that the first step (binding) contributes a more significant, and sometimes major, share of the activation energy. To support this theory, we have synthesized a large variety of test-tube models which simulate the bound substrate by being frozen into a single, favorable conformation and by having the interacting groups brought into the closest possible juxtaposition (stereopopulation control). These compounds undergo intramolecular reactions at rates comparable to those catalyzed by enzymes, and show that the protein raises both the entropic and enthalpic components of the substrate by binding it in a single, rigid conformation. Recent work has involved the synthesis of compounds designed (1) to evaluate the flexibility of conformationally frozen carbon chains by ring-ring interconversion and (2) to study steric and electronic effects of 1H and 13C nmr spectra through space rather than through covalent bonds. Studies with several series of aromatic systems have shown that both reaction kinetics and spectral properties are linearly related to the van der Waals size of crowding substituents. The upper limits of energy-related steric crowding could not be evaluated, however, because of inability to introduce the very bulky iodo substituent. After considerable effort, this goal has now been reached; kinetic and spectral studies are in progress. As part of our studies of practical application of stereopopulation control, we are currently exploring the use of o-nitroaryl derivatives of biogenic amines and antibiotics as prodrugs. The intent is to facilitate passage from gut to circulatory system to brain by temporary masking of charge within the molecule.